This project proposes clinical trials in allogeneic hematopoietic cell (HSC) transplantation designed to address the need for a) more effective, tolerable preparatory regimens particularly for patients receiving HSC grafts from unrelated and HLA non-identical donors b) disease targeted adoptive therapies for eradication of recurrent leukemia that abrogates risks of severe, irreversible GVHD and the c) more effective, approaches for stimulating early recovery of general and pathogen specific immunity. Specific Aim 1 presents four trials testing novel and potentially improved myeloablative regimens used with T-cell depleted HSC transplants for the treatment of leukemia, including 1a) HLA compatible related or unrelated SBA-E- BM transplants after HFTBI, thiotepa and cyclophosphamide for treatment of young patients (<18 yrs of age) with acute leukemia; 1b) HLA-matched related or unrelated CD34+E- PBSC or (SBA-E-BM) transplants after HFTBI, thiotepa and fludarabine and low dose ATG for treatment of adults with high risk acute leukemias, CML in chronic phase, and high risk NHL in secondary or greater remission; 1c) HLA-haplotype disparate related CD34+E-PBSC transplants after the same cytoreduction as in 1b, for patients with chemo-responsive leukemias in second-degree or greater remission who lack an HLA compatible related/unrelated donor; and 1d) an evaluation of a chemotherapeutic preparative regimen combining busulfan, melphalan and fludarabine and low dose ATG for T-cell depleted transplants administered to patients with leukemias at high risk of relapse who cannot receive TBI. Under Specific Aim 2, we propose two trials of non-myeloablative regimens combined with disease targeted monoclonal antibodies to improve outcomes of HLA-related unmodified PBSC transplants applied to patients who by virtue of prior therapy or co-morbidities cannot receive myelo-ablative cytoreduction. For CD33+ AML and CML, we will evaluate 90Y HuM195 coupled with low dose TBI and fludarabine; for CD52+ lymphoid leukemias and lymphomas, we will test CAMPATH-1H combined with melphalan and fludarabine. Under Specific Aim 3, we will evaluate bcr/abl peptide vaccinations prior to and following donor leukocyte infusions as an approach to induce CML-specific immunity and increase the proportion of patients achieving molecular remissions at low T-cell doses unlikely to induce GVHD. Under Specific Aim 4, we propose a phase I/II trial of donor derived EBV sentitized T-cells transduced with a dicistronic retroviral vector, NIT, encoding a mutant human nerve growth factor receptor and HLV-TK in the treatment of EBV lymphomas. Lastly, under Specific Aim 5, we will evaluate whether growth hormone can stimulate recovery of thymopoiesis and immunity in the post transplant period.